Nitrous oxide-based versus nitrous oxide-free general anaesthesia and accidental awareness in surgical patients

1 Nitrous oxide-based versus nitrous oxide-free general anaesthesia and accidental awareness in surgical patients: an abridged Cochrane systematic review J Hounsome,1 J Greenhalgh,2 O Schofield-Robinson,3 S.R Lewis,3 T.M Cook,4 A.F Smith5 Research Fellow, Liverpool Reviews and Implementation Group, University of Liverpool, Liverpool, UK Senior Research Fellow, Liverpool Reviews and Implementation Group, University of Liverpool, Liverpool, UK Research Associate, Patient Safety Research Unit, Royal Lancaster Infirmary, Lancaster, UK Consultant in Anaesthesia and Intensive Care Medicine, Royal United Hospital Bath NHS Foundation Trust, Bath, UK, Honorary Professor of Anaesthesia, School of Clinical Sciences, University of Bristol University of Bristol, Bristol, UK Consultant Anaesthetist, Department of Anaesthesia, Royal Lancaster Infirmary, Lancaster, UK Correspondence to: O Schofield-Robinson, Research Associate, Patient Safety Research Unit, Royal Lancaster Infirmary, Pointer Court 1, Lancaster, LA1 4RP, United Kingdom Email: o.schofieldrobinson@mbht.nhs.uk Keywords: nitrous oxide, awareness, systematic review Short title: Effect of nitrous oxide-based versus nitrous oxide-free general anaesthesia on accidental awareness Summary Accidental awareness during general anaesthesia can arise from a failure to deliver sufficient anaesthetic agent, or from a patient’s resistance to an expected sufficient dose of such an agent Awareness is ‘explicit’ if the patient is subsequently able to recall the event We conducted a systematic review into the effect of nitrous oxide used as part of a general anaesthetic on the risk of accidental awareness in people over the age of five years undergoing general anaesthesia for surgery We included 15 randomised controlled trials, 14 of which, representing a total of 3439 participants, were included in our primary analysis of the frequency of accidental awareness events The awareness incidence rate was rare within these studies, and all were considered underpowered with respect to this outcome The risk of bias across all studies was judged to be high, with a universally high performance bias risk and with 76 per cent of studies failing to adequately conceal participant allocation We considered the available evidence to be of very poor quality There were a total of three accidental awareness events reported in two studies, one of which reported that the awareness was the result of a kink in a propofol intravenous line There were insufficient data to conduct a meta or sub-group analysis and there was insufficient evidence to draw outcome-related conclusions We can, however, advise that future studies focus on potentially high-risk groups such as obstetric or cardiac surgery patients; or those receiving neuromuscular blocking drugs or total intravenous anaesthesia This article is based on a Cochrane Review published in the Cochrane Database of Systematic Reviews (CDSR) 2016, Issue DOI: 10.1002/14651858 No.: CD011052 (see www.thecochranelibrary.com for information) Cochrane Reviews are regularly updated as new evidence emerges and in response to feedback, and the CDSR should be consulted for the most recent version of the review Summary: 250 words Main body: 3530 words Introduction Accidental awareness during general anaesthesia can be described as unintentional consciousness during a procedure in which general anaesthesia is intended The Michigan awareness classification instrument describes levels of awareness ranging from no awareness through broken auditory perceptions to awareness of paralysis and pain Such awareness may be unpleasant, and can lead to long-term psychological effects Through the Brice protocol , or a derivative of it, many studies, both randomised controlled trials (RCT) and observational studies, have found that possible or definite awareness occurred in one to two cases per 1000 general anaesthetics However, other methodologies have identified a considerably lower rate of accidental awareness Bispectral index (BIS) monitoring to measure electroencephalogram (EEG) has been investigated as a possible way of limiting accidental awareness While BIS usage has demonstrated mixed results , BIS monitors (and other EEG based monitors) are still included in UK guidelines for some anaesthetic settings Risk factors for accidental awareness, then, are not fully understood, but are known to be linked with an (unintentional or intentional) inadequate dose of an anaesthetic agent These are not easily explored, however, as studying uncommon events using RCTs or less rigorous study designs can present problems of statistical power and confounding variables Nitrous oxide gas is a weak anaesthetic agent, but is commonly used with oxygen and other agents such as a volatile anaesthetic agent for the maintenance of anaesthesia The challenges of investigating effects from sparse data affect not only trials but reviews seeking to synthesise these rare events The present review was conceived partly in response to a 1996 review by Tramer and colleagues, which suggested that there may be a potential increase in the risk of accidental awareness associated with a nitrous oxide-free anaesthetic Nitrous oxide has been linked by some other studies and authors with a potential decreased risk of explicit awareness , while other studies have reported the opposite Nitrous oxide differs from other conventional anaesthetic agents in that it is a N-methyl-D-aspartate (NMDA) antagonist as opposed to a gamma-aminobutyric acid (GABA) agonist , but exactly why nitrous oxide might affect the risk of accidental awareness is not known It has been suggested that nitrous oxide might decrease the risk of accidental awareness because it is a more powerful memory suppressant than equivalent agents , or because of more rapid pharmacokinetics, which enables clinicians to better predict the dose received by the patient Alternatively, there may be antagonism between anaesthetic agents which act on GABA receptors and the anti-nociceptive effects of nitrous oxide, which may increase the risk of awareness At present we not know whether nitrous oxide affects awareness due to a direct action on the brain, alters the action of other anaesthetic agents to affect awareness, or has no effect on awareness The use of brain activity monitors in patients anaesthetised using nitrous oxide is complex, since NMDA antagonists suppress cortical EEG less than GABAergic agents and it has been shown that BIS values not change during nitrous oxide sedation Using brain monitors to titrate nitrous oxide-based anaesthesia may therefore lead to an increase in dose and inappropriately deep anaesthesia Despite conflicting evidence as to its effects, nitrous oxide is still used widely In a 2015 national survey, nitrous oxide was noted to be used in 29% of all general anaesthetics (i.e approximately 770,000 cases out of three million total cases per year in the UK), including in 45% of paediatric cases and 71% of general anaesthetic for Caesarean section There has been recent concern about the possible adverse consequences of using nitrous oxide as an anaesthetic agent , but this has largely been redressed by the ENIGMA-2 study The primary objective of this review is to assess the effect of the inclusion of nitrous oxide as part of a general anaesthetic, on the risk of accidental awareness in patients aged five years and older undergoing a surgical procedure Methods A protocol for conducting this systematic review and the full published review are available elsewhere We considered all RCTs including quasi-randomised studies and clusterrandomised studies We included trials of participants aged five years or older, receiving general anaesthesia for any type of surgery Only studies that included a prospective method for detecting (and reporting) accidental awareness were included We included trials in which participants receiving general anaesthesia that included nitrous oxide for maintenance at a concentration of ≥30% were compared with participants receiving no nitrous oxide The intervention group must have received nitrous oxide in conjunction with an additional anaesthetic An additional anaesthetic could have been an inhalation anaesthetic (such as sevoflurane, enflurane or isoflurane), or an intravenous anaesthetic (such as propofol) We excluded studies in which nitrous oxide was the sole form of anaesthetic We included studies in which the additional anaesthetic agent for the intervention and comparison group was at the discretion of the anaesthetist as differences between groups in the anaesthetic delivery would be accounted for by randomisation We excluded studies where participants were randomised to different anaesthetic techniques apart from the administration of nitrous oxide, for example inhalation versus intravenous anaesthetic Because depth of anaesthesia can affect the likelihood of accidental awareness, we excluded studies where the two arms had different apparent depths of anaesthesia We used the reported minimum alveolar concentration (MAC) to access and assess this information All MACs of different agents, including nitrous oxide, were considered additive in determining equivalence of anaesthetic depth between arms of each study To determine equality of depth in the study using TIVA as the additional agent we consulted TM Cook and AF Smith for assistance We had intended to conduct a subgroup analysis of studies which used specified additional anaesthetic agents, such as propofol, as part of an established protocol, but we did not identify sufficient studies to so The primary outcome was explicit accidental awareness Precise definitions for accidental awareness vary , so for studies which divide awareness in this way, we included probable and definite awareness events only We classified reported events with a high probability of occurring before or after anaesthesia as no awareness We included studies which used the Brice protocol for ascertainment or those with other direct questioning methods, including over a shorter period We excluded studies which relied on unsolicited self-reports of accidental awareness There were no secondary outcomes We searched the following electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid) and EMBASE (Ovid) We applied the Cochrane highly sensitive filter for RCTs in MEDLINE and EMBASE The search strategy used for MEDLINE can be found in the published protocol We also searched the following trial registers: www.clinicaltrials.gov, the WHO International Clinical Trials Registry Platform (www.who.int/ictrp/network/en/) and Current Controlled Trials (www.isrctn.com/) We also conducted forward citation searches on the Tramer review article , and backwards citation searches on two studies using the Scopus and Web of Science databases The searches were performed on 9th December 2015 There were no language restrictions Two of three authors screened all titles and abstracts to remove studies that were very unlikely to be eligible We piloted 100 titles before reviewing all titles in order to clarify criteria for discarding articles at this stage If no abstract was available but the title was possibly relevant, we obtained the full text of the article When we had screened all titles and abstracts, two of the same three authors reviewed the full texts of potentially relevant titles Any differences which could not be resolved were referred to an additional author This process is summarised in Figure All extracted data were then transferred into Review Manager software Two authors used the Cochrane risk of bias tool to independently assess the following: random sequence generation; allocation concealment; blinding of participants and personnel (performance bias); blinding of outcome assessors (detection bias); incomplete outcome data; other sources of bias Studies were judged to be at a high risk of attrition bias in the incomplete outcome data domain if they had a participant attrition rate of >20% The single outcome in this review is a dichotomous outcome (occurrence of accidental awareness) For the benefit of analytic utility we divided outcome data into three groups based on separate time points: a) all data for accidental awareness irrespective of assessment time point; b) studies which assessed accidental awareness in recovery; c) studies which assessed accidental awareness 24 hours post-operatively We used the calculator in Review Manager software to calculate odds ratios (ORs) with 95% confidence intervals (CIs) We used Peto odds ratios as accidental awareness is a rare event and we anticipated that event data would be sparse Results We retrieved 8976 records from the electronic databases and 226 from citation and trial searches After duplicates, were removed we screened 4539 records for inclusion Of these, we selected 225 for full-text review of which 188 papers were excluded because they did not meet our eligibility criteria After this process we identified a further 15 papers, reporting on 12 studies , which also required exclusion for not meeting these criteria Of these 12 studies, six did not include an intervention or comparator relevant to this review , for five studies the depth of anaesthesia differed between study arms and two papers reported on the ENIGMA II study , which did not measure accidental awareness Through this process we identified 22 publications covering 15 studies for inclusion in the review One study , while included in the qualitative synthesis of the present review, could not be included in the primary analysis as the number of participants in each group was not reported 11 studies included a single comparison of an arm with nitrous oxide and an arm without nitrous oxide , while four studies included more than one comparison Of these multi-arm studies, three included four arms and one included three arms The anaesthetic agents used in the studies varied, with seven using propofol , three using sevoflurane , three using isoflurane and two using desflurane One study left other anaesthetics to the discretion of anaesthetists Concentrations of nitrous oxide used in the included studies also varied, with two studies using 50% , four studies 60% , one study 65% , one study 66% , two studies 67% ) and five studies 70% The methods used by anaesthetists to monitor the depth of anaesthesia varied considerably Eight studies used clinical signs/haemodynamic changes , four studies delivered fixed concentrations and two studies used clinical experience but with no criteria stated Three studies used EEG-based monitoring; one as the sole monitor of anaesthetic depth , two in addition to other forms of monitoring None of the included studies had accidental awareness as a primary outcome, and the methods of accidental awareness assessment varied across the studies One study used the Brice protocol , and two studies used a modified version of the Brice protocol A further two studies used a structured questionnaire All other studies questioned participants more informally The timing of assessment also varied, with seven studies assessing accidental awareness whilst participants were in recovery and in ten studies 24 hours post-operatively One study reported that accidental awareness was assessed at discharge, but also reported that data were collected two hours after anaesthesia The risk of bias within and across studies varied considerably (Table 1) Methods of random sequence generation were generally poorly reported among studies, with six studies failing to provide sufficient detail Nine studies provided adequate information on randomisation methods and we judged these to have a low risk of bias across studies 11 studies failed to provide sufficient information regarding efforts to conceal group allocation For reasons of patient safety, the anaesthetist could not be blinded to the intervention; therefore, we judged all studies to be at a high risk of performance bias We judged seven studies to be at a low risk of detection bias; authors of these studies reported that investigators and/or participants were blinded to group allocation No studies reported a complete absence of blinding Eight studies reported no participant attrition during the study period One study reported significant (59%) participant attrition, and was marked as high risk As pre-specified accidental awareness outcome was part of the inclusion criteria for this review, we judged that selective reporting bias was not a relevant criterion We did not identify any other sources of bias across the studies 8 Synthesis of results Of the 15 studies, 14 were included in the primary analysis Four studies included more than one comparison and are therefore included in the analysis for each comparison Due to lack of sufficient data and imprecise reporting, it was not possible to adequately sub-divide the events by time points as intended A total of three accidental awareness events were reported in the 14 analysed studies (3439 participants) All three events were reported by patients who received nitrous oxide-based anaesthesia There were two events in the ENIGMA study We could not determine from the published paper when the accidental awareness was assessed, i.e in recovery or at 24 hours post-operatively The third event, in Arellano 2000 , was reported by the study authors to be the result of a technical failure in the anaesthesia process (a possible kink in the propofol intravenous line) rather than a result of the pharmacological intervention This assessment took place after anaesthesia, but there was no specific time point recorded Given the very small number of events from a similarly small number of studies, we judged that it was not appropriate to pool data or conduct a meta-analysis for this outcome Using GRADE software principles , we downgraded the quality of the evidence by one level (poor), due to concerns about the risk of bias, and by two levels (very poor) due to concerns around imprecision (Table 2) Discussion We included 15 studies, of which 14 were included in the primary analysis In these studies 3439 participants were randomised to receive anaesthetic agents including nitrous oxide, as part of a general anaesthetic A total of three accidental awareness events were reported in two studies We considered pooling of data through meta-analyses and subgroups to be inappropriate given this paucity of data It is therefore not possible to draw any direct conclusions about the primary outcomes What we must conclude, then, is that the question of the risk of accidental awareness during general anaesthesia with or without nitrous oxide is left unanswered None of the included trials were designed to measure accidental awareness as a primary outcome, and all were underpowered to study this outcome We judged the evidence relating to the impact of use of nitrous oxide on the risk of accidental awareness to be of very low quality 9 As our review failed to find sufficient evidence to draw any outcome-related conclusions, it is not possible for us to confirm or contest any findings from other reviews or studies We cannot determine whether the use of nitrous oxide in general anaesthesia increases, decreases, or has no effect on the risk of accidental awareness The review and meta-analysis by Tramer and colleagues in 1996, which hitherto is the only known review to directly address the association between nitrous oxide usage and incidence of accidental awareness, reported that there was an increased risk of awareness in patients who did not receive nitrous oxide The data in this 1996 review however, are less than reliable considering that the review was designed to investigate the association between nitrous oxide and nausea/vomiting, meaning that there was no discrimination of studies by anaesthetic agent Significantly, two studies included in the Tramer review which reported incidents of accidental awareness in the nitrous oxide-free group were not included in this review because the study authors did not report a structured method to identify awareness While some, more narrative, reviews have incorporated the findings of the Tramer review, a recent large observational study did not find an association between nitrous oxide and accidental awareness The findings of the present review have wider implications for both the synthesis and study of rare outcomes and adverse events in systematic reviews and trials, respectively The issues surrounding sparse data sets and reliability in reviews has been explored in a recentlypublished editorial - the conclusions of which emphasise the need for methodological rigour and due caution in interpretation Regarding trials, assuming an incidence of accidental awareness of 1/500 patients receiving general anaesthesia and that nitrous oxide leads to a 50% increase in awareness, an RCT would need to have over 11,737 participants in each arm to have 80% power to detect the increase at 5% significance level This would increase to 23,511 participants in each arm if the incidence was assumed to be 1/1000 A recent RCT with almost 11,000 in each arm investigating the use of BIS on accidental awareness was terminated due to futility, with no significant difference in incidence being detected between the arms If such studies were to be done, it may be advisable to focus on higher-risk groups such as those undergoing Caesarean section, cardiac surgery, or receiving neuromuscular blocking drugs or total intravenous anaesthesia (TIVA) However, it is not clear that the costs involved would be justified Without such studies, though, it is unlikely that any future metaanalyses would be able to draw any implications for clinical practice 10 Observational studies have the potential to address this issue, and the NAP5 study, which examined new spontaneous reports of accidental awareness arising from approximately three million general anaesthetics, found no association between accidental awareness and nitrous oxide use The lower overall incidence of reports of awareness (1/19,600) reflects that ascertainment relied on spontaneous reports of accidental awareness but there is no obvious reason to assume that any association with nitrous oxide would be distorted by under-reporting The routine use of direct questioning in conjunction with routine data has the potential to provide further data In the NAP5 study, obstetric surgery patients were identified as being as being at a potentially higher risk of accidental awareness than other patient groups undergoing anaesthesia A future source of evidence addressing this particular group may come from the planned observational study Direct REporting of Awareness in MaternitY patients (DREAMY) Acknowledgements We would like to thank Amanda Nicholson for her work on the early drafts of this review; Rodrigo Cavallazzi, Cathal Walsh, Kate Leslie, Richard P Dutton, James Palmer and Patricia Tong and other members of the Cochrane Anaesthesia, Critical and Emergency Care group for their help and editorial advice during the preparation of this systematic review We would like to thank Eleanor Kotas for her assistance in undertaking searches of trial registries and citation tracking and Gareth Jones for assistance with finding the full texts of publications Competing Interests This review was funded by an NIHR Cochrane Collaboration Programme Grant ‘Enhancing the safety, quality and productivity of perioperative care’ Project Ref: 10/4001/04., UK No competing interests declared References 11 Legend to figure Figure 1: Flow chart of search method and study selection 12 Table Summary of risk of bias Study Sequence generation (selection bias) Allocation concealment (selection bias) Blinding of participants and personnel (performance bias)* Blinding of outcome assessors (detection bias) Incomplete outcome data (attrition bias) Selective reporting (reporting bias) Aceto 2002 (51) Low Unclear High Low Low Low Albertin 2005 (52) Low Unclear High Unclear Unclear Low Arellano 2000 (53) Low Low High Low High Low Crawford 1998 (54) Low Unclear High Low Low Low Dedola 2008 (55) Low Unclear High Unclear Low Low Girardi 1994 (56) Unclear Unclear High Unclear Low Low Handa 2010 (57) Unclear Unclear High Unclear Low Low Handa-Tsutsui (58) Low Unclear High Unclear Low Low Heath 1996 (59) Unclear Unclear High Low Unclear Low Lindekaer 1995 (60) Unclear Unclear High Unclear Low Low Myles 2007 (31) Low Low High Low Low Low Ngan Kee 2002 (61) Low Low High Low Low Low Singh 2011 (62) Low Unclear High Low Low Low Sukhani 1994 (63) Unclear Unclear High Low Low Unclear 13 Vanacker 1999 (64) Unclear Low High Unclear Low Low *For safety reasons, it was not possible to blind anaesthetists to the intervention Table GRADE summary of findings Patient population: surgical patients Setting: Seven studies in Europe, three in North America, two in Japan, one in India, one in Hong Kong and one international multi centred Intervention: Nitrous oxide-based Comparison: Nitrous oxide -free Anticipated absolute effects* (95% CI) Relative No of Quality of the Outcomes participants evidence Comments Risk without Nitrous Risk with Nitrous effect (95% CI) (studies) (GRADE) oxide oxide Accidental awareness Study population ⊕⊝⊝⊝ 3439 Results not pooled due to rarity Overall not estimable (14 RCTs) of events VERY LOW not pooled not pooled assessed with: Any Accidental awareness - In Study population ⊕⊝⊝⊝ 263 Results not pooled due to rarity recovery not estimable (5 RCTs) of events VERY LOW not pooled not pooled assessed with: Any Accidental awareness - 24 Study population ⊕⊝⊝⊝ hours 556 Results not pooled due to rarity not estimable assessed with: Any (7 RCTs) VERY LOW of events not pooled not pooled follow-up: days *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI) GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect The anaesthetist delivering the anaesthetic was aware of the allocation in all studies, as this is essential for patient safety, so we rated all studies at high risk of performance bias  ... interpretation Regarding trials, assuming an incidence of accidental awareness of 1/500 patients receiving general anaesthesia and that nitrous oxide leads to a 50% increase in awareness, an RCT... words Main body: 3530 words Introduction Accidental awareness during general anaesthesia can be described as unintentional consciousness during a procedure in which general anaesthesia is intended... receiving general anaesthesia for any type of surgery Only studies that included a prospective method for detecting (and reporting) accidental awareness were included We included trials in which